Abstract This application is for the Continuation of the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) clinical center at Saint Louis University and its pediatric component at Baylor University. The NASH Clinical Research Network (NASH CRN) has been sponsored by the NIDDK since 2002 with renewals in 2009 and 2014. Nonalcoholic fatty liver disease (NAFLD) affects more than one out of three adults and one out of five children the U.S. NAFLD, and especially its most severe subset nonalcoholic steatohepatitis (NASH), may lead to cirrhosis and primary liver cancer resulting in death or liver transplant and substantial health burdens and costs. The NASH CRN is ideally and uniquely positioned to impact the growing public health significance of NASH that can only be addressed via a large research consortium. The primary objective of the NASH CRN is to perform clinical trials of therapeutic agents for NASH and NAFLD in adults and children. A closely linked and high priority secondary objective is to conduct translational research in NASH and NAFLD focusing on the pathogenesis that will provide the basis for understanding the natural history and developing means of better diagnosis, prevention, treatment, and clinical management. In the next phase of the NASH CRN, the adult and pediatric therapeutic trials initiated during the previous funding cycles will be completed and new therapeutic trials, including phase 2a proof of mechanism and phase 2b clinical trials will be initiated to develop evidence- based treatment options that are safe, effective, simple, cost-effective and broadly applicable. The longitudinal cohort of adults and children with NAFLD collected over the past decade will be extended to prospectively define the natural history of the disease, the cardiovascular and metabolic risk factors, and will aid in biomarker discovery and validation. This cohort will also facilitate the development and validation of non-invasive techniques to identify those with NASH, predict who will respond to treatments, and identify factors affecting disease progression. The treatment trial proposed in this application is a phase 2a trial of a dietary supplement called tributyrin. Tributyrin makes up about 3% of butter and is a prodrug of butyric acid. Butyric acid is an important metabolite produced by bacteria in the GI tract during their normal metabolism of dietary fiber. Butyric acid has been shown to be the primary energy source for the layer of cells that line the colon where it promotes the function of these cells and prevents harmful bacterial products from entering the blood and damaging the liver. It has also been found to have beneficial effects on metabolism throughout the body. Animal data supports the rationale for studying butyric acid, or its precursor tributyrin, in treating NASH but human data are very limited. Additional translational studies are proposed in this application to mechanistically understand the benefits of tributyrin treatment gut permeability and whole-body metabolism. The NASH CRN is poised to continue its major impact on the field and directly advance the mission of the National Institutes of Health to improve the health of the public.